In this grant application we propose to continue a wide-ranging program of research on the molecular bases of the nature and specificity of nucleic acid-protein interactions in forming physiologically-relevant genome control systems. Some studies on model systems relevant to the structure and stability of the conformation of biological macromolecules will also be carried on. In the area of nucleic acid-protein interactions, we plan to examine further the interactions of E. coli lac repressor with small molecule inducers and operator and non-operator DNA, in an attempt to further elucidate the thermodynamic, kinetic and molecular components of this part of the lac operon control system. Small molecule models (e.g., the binding of tetraalkylammonium ions to AT and GC base-pairs) will also be studied further in attempting to elucidate the origins of base-pair sequence specific recognition by site-specific DNA binding proteins such as lac repressor. Studies will also be continued on the kinetics and equilibria of the interaction between DNA and "melting proteins" (defined as proteins which bind preferentially to single-stranded polynucleotide conformation and thus destabilize the double helix). The physico-chemical interactions of melting proteins such as T4-coded gene 32-protein with other components of DNA replication complexes will also be studied as well. Recognition and discrimination mechanisms for specific DNA sequences will also be examined in restriction-modification enzymes and appropriate model systems. Studies on the nucleic acid binding interactions and specificity of E.coli S1 ribosomal protein will be continued as well. The emphasis throughout these studies will be on the elucidation of general principles required for a molecular understanding of genome regulatory systems in prokaryotes and eukaryotes.